Camptothecin (abbreviated as CPT hereinafter, J. Am. Chem. Soc., 1966, 88, 3888), which was extracted and isolated from camptotheca acuminata by Wall et al. for the first time, is a pyrrole[3,4-b]quinoline alkaloid with the structure of
It is a pentacyclic structure with an S-type chiral center at the 20-position on Ring E and a lactone structure near the chiral center. Although camptothecin has certain therapeutic effect on gastric cancer, rectal cancer and the like, its clinical research is limited because of its poor solubility in water and toxic side effect.
An intensive research has been made on the CPT molecular structure modifications to obtain CPT derivatives with higher activity and lower toxicity. Accordingly, a large number of CPT compounds with good effects have been synthesized. Meanwhile, it has been found that the antitumor activity can be enhanced by introducing a suitable group at the 9-position of 10-hydroxy camptothecin. For example, Topotecan commercially available at present is such a compound.
Unlike common inorganic bases and organic bases, although CPT compounds are alkaloids, their salts have poor water-solubility. Generally, there are two schemes used to solve the water solubility problem. One is to introduce a water-soluble group which can be salified, such as amino groups, into the CPT compounds, and Topotecan is such an example. The other is to introduce a provisional water-soluble group which can be dissociated in vivo into the CPT compounds, and Irinotecan (compound 4, CPT-11), a water-soluble CPT drug, is such an example.
During screening for antitumor drugs, surprisingly, the present inventors have found that the compounds obtained by introducing lower alkyl to the 9-position of 10-hydroxy camptothecin (as represented by the following formula II, wherein R1 is H, C1-C4 alkyl, C1-C4 branched alkyl, or C1-C4 alkyl substituted by hydroxy and/or amino group) have excellent antitumor activities. Among these compounds, some have excellent therapeutic effects on solid tumor xenografts in tumor-bearing nude mice and higher therapeutic indices, thereby indicating the prospect of these compounds for further development as antitumor drugs.

However, the compounds represented by formula II also have the problem of poor solubility in water.